Interaction of angiogenesis inhibitor TNP-470 with basic fibroblast growth factor receptors.

TNP-470 is a synthetic analogue of fumagillin that acts as a potent angiogenesis inhibitor. Recently, our laboratory demonstrated that systemic administration of TNP-470 (5.0 mg/kg) decreased the rate of cutaneous wound healing by greater than 20%. In this study, we tested the hypothesis that TNP-470 interferes with the wound repair-stimulating action of basic fibroblast growth factor (bFGF) by competing with endogenous bFGF for its binding sites on the receptor protein. The influence of TNP-470 was examined in vitro in a ligand competition assay of high- and low-affinity receptor binding to (125)I-bFGF in NIH/3T3 cells. Results demonstrated that recognition of (125)I-bFGF by low-affinity growth factor binding sites was significantly decreased (P < 0.01) in the presence of TNP-470. However, TNP-470 inhibition of radiolabeled bFGF binding to high-affinity sites was not significantly affected (P = 0.07). In view of recent studies demonstrating that the low-affinity receptors of bFGF were heparan sulfate proteoglycans, we suggest that the influence of TNP-470 on diminished wound healing is due to its direct recognition by these molecules.

[1]  G. Anderson,et al.  Angiogenesis inhibitor TNP-470 inhibits murine cutaneous wound healing. , 1999, The Journal of surgical research.

[2]  G. Neufeld,et al.  Vascular endothelial growth factor (VEGF) and its receptors , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[3]  P. Gleizes,et al.  Cell Release of Bioactive Fibroblast Growth Factor 2 by Exon 6-encoded Sequence of Vascular Endothelial Growth Factor* , 1997, The Journal of Biological Chemistry.

[4]  W. Bornmann,et al.  The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[5]  K. Biemann,et al.  Methionine aminopeptidase (type 2) is the common target for angiogenesis inhibitors AGM-1470 and ovalicin. , 1997, Chemistry & biology.

[6]  J. Slavin,et al.  Fibroblast growth factors: at the heart of angiogenesis. , 1995, Cell biology international.

[7]  A. Yayon,et al.  Engineering of fibroblast growth factor: alteration of receptor binding specificity. , 1995, Biochemistry.

[8]  W. Border,et al.  Transforming Growth Factor β in Tissue Fibrosis , 1994 .

[9]  R. Martuza,et al.  AGM-1470 inhibits the growth of human glioblastoma cells in vitro and in vivo. , 1994, Neurosurgery.

[10]  L. Broemeling,et al.  Application of Basic Fibroblast Growth Factor May Reverse Diabetic Wound Healing Impairment , 1993, Annals of plastic surgery.

[11]  D. Givol,et al.  Complexity of FGF receptors: genetic basis for structural diversity and functional specificity , 1992, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[12]  E. Edelman,et al.  Transforming growth factor beta 1 stimulates the production of basic fibroblast growth factor binding proteoglycans in Balb/c3T3 cells. , 1992, The Journal of biological chemistry.

[13]  M. Salmivirta,et al.  Growth factors induce 3T3 cells to express bFGF-binding syndecan. , 1992, The Journal of biological chemistry.

[14]  M. Hayman,et al.  Characterization of the FGFR‐3 Gene and Its Gene Product , 1991, Annals of the New York Academy of Sciences.

[15]  M. Klagsbrun,et al.  A dual receptor system is required for basic fibroblast growth factor activity , 1991, Cell.

[16]  B. Olwin,et al.  Requirement of heparan sulfate for bFGF-mediated fibroblast growth and myoblast differentiation , 1991, Science.

[17]  J. Partanen,et al.  FGFR‐4, a novel acidic fibroblast growth factor receptor with a distinct expression pattern. , 1991, The EMBO journal.

[18]  Jeffrey D. Esko,et al.  Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor , 1991, Cell.

[19]  D. Rifkin,et al.  Monospecific antibodies implicate basic fibroblast growth factor in normal wound repair. , 1989, Laboratory investigation; a journal of technical methods and pathology.

[20]  V. Fried,et al.  Purification and complementary DNA cloning of a receptor for basic fibroblast growth factor. , 1989, Science.

[21]  A. Sommer,et al.  Recombinant basic fibroblast growth factor accelerates wound healing. , 1988, The Journal of surgical research.

[22]  R. Weinberg,et al.  Basic fibroblast growth factor fused to a signal peptide transforms cells , 1988, Nature.

[23]  D. Moscatelli,et al.  High and low affinity binding sites for basic fibroblast growth factor on cultured cells: Absence of a role for low affinity binding in the stimulation of plasminogen activator production by bovine capillary endothelial cells , 1987, Journal of cellular physiology.

[24]  D. Gospodarowicz,et al.  Basic and acidic fibroblast growth factors interact with the same cell surface receptors. , 1986, The Journal of biological chemistry.

[25]  Usa Serono Symposia,et al.  Growth factors and wound healing : basic science and potential clinical applications , 1997 .

[26]  A. Baird.  The Regulation of Basic Fibroblast Growth Factor (FGF-2) Through Limited Bioavailability , 1997 .

[27]  J. Smith,et al.  Fibroblast growth factors and their receptors. , 1997, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[28]  E. Pasquale,et al.  Different members of the fibroblast growth factor receptor family are specific to distinct cell types in the developing chicken embryo. , 1993, Developmental biology.